We have investigated the autocrine/paracrine functions of insulin-like growth factors I and II (IGF-I and -II) in the central nervous system, reproductive system, and kidney in both rodents and humans. Our major experimental methods include in situ hybridization, immunocytochemistry and ligand-binding autoradiography; these techniques are employed to identify the cellular sites of synthesis of the growth factors. In addition, we have used these same methods to determine the cellular localization of the receptors which mediate IGF actions and to map the distribution of the six different high-affinity IGF binding proteins which are known to modulate the interaction of IGF-I and -II with their receptors. Our studies have focused on normal embryonic development as well as a number of different physiological and pathophysiological situations in which IGFs seem to be critically important. Important results of these studies during the past year include: 1) Evidence for the expression of hybrid insulin: IGF receptors which have predominantly metabolic effects but demonstrate higher affinity for IGF-I than insulin. This hybrid receptor is preferentially expressed in brain and kidney. 2) A new member of the IGF/insulin receptor family, termed the insulin receptor-related receptor (IRR) has been identified, and we have shown that it is selectively colocalized with the high-affinity nerve growth factor (NGF) receptor. Data suggests that this new receptor is physically or functionally linked with the NGF receptor and together they are involved in determining the survival of sensory and sympathetic neurons. 3) IGF-I (in the rodent) and IGF-II (in the human) appear to be critical determinants of ovarian follicular maturation and ovulation, and expression of one of the specific (inhibitory) IGF binding proteins by a follicle appears to predict follicular atresia and oocyte demise. Furthermore, there is intense IGF-I receptor expression in human oocytes and spermatocytes. These findings have very significant clinical implications in terms of the potential utilization of IGFs or IGF or analogs to selectively regulate cerebral and renal metabolism and both male and female fertility.